Intrinsic dopamine and acetylcholine dynamics in the striatum of mice.

External rewards such as food and money are potent modifiers of behaviour1,2. Pioneering studies established that these salient sensory stimuli briefly interrupt the tonic discharge of neurons that produce the neuromodulators dopamine (DA) and acetylcholine (ACh): midbrain DA neurons (DANs) fire a burst of action potentials that broadly elevates DA in the striatum3,4 at the same time that striatal cholinergic interneurons (CINs) produce a characteristic pause in firing5,6. These phasic responses are thought to create unique, temporally limited conditions that motivate action and promote learning7-11. However, the dynamics of DA and ACh outside explicitly rewarded situations remain poorly understood. Here we show that extracellular DA and ACh levels fluctuate spontaneously and periodically at a frequency of approximately 2 Hz in the dorsal striatum of mice and maintain the same temporal relationship relative to one another as that evoked by reward. We show that this neuromodulatory coordination does not arise from direct interactions between DA and ACh within the striatum. Instead, we provide evidence that periodic fluctuations in striatal DA are inherited from midbrain DANs, while striatal ACh transients are driven by glutamatergic inputs, which act to locally synchronize the spiking of CINs. Together, our findings show that striatal neuromodulatory dynamics are autonomously organized by distributed extra-striatal afferents. The dominance of intrinsic rhythms in DA and ACh offers new insights for explaining how reward-associated neural dynamics emerge and how the brain motivates action and promotes learning from within.

Hippocampal 5-HT Input Regulates Memory Formation and Schaffer Collateral Excitation.

The efficacy and duration of memory storage is regulated by neuromodulatory transmitter actions. While the modulatory transmitter serotonin (5-HT) plays an important role in implicit forms of memory in the invertebrate Aplysia, its function in explicit memory mediated by the mammalian hippocampus is less clear. Specifically, the consequences elicited by the spatio-temporal gradient of endogenous 5-HT release are not known. Here we applied optogenetic techniques in mice to gain insight into this fundamental biological process. We find that activation of serotonergic terminals in the hippocampal CA1 region both potentiates excitatory transmission at CA3-to-CA1 synapses and enhances spatial memory. Conversely, optogenetic silencing of CA1 5-HT terminals inhibits spatial memory. We furthermore find that synaptic potentiation is mediated by 5-HT4 receptors and that systemic modulation of 5-HT4 receptor function can bidirectionally impact memory formation. Collectively, these data reveal powerful modulatory influence of serotonergic synaptic input on hippocampal function and memory formation.

Chronic Nicotine Mitigates Aberrant Inhibitory Motor Learning Induced by Motor Experience under Dopamine Deficiency.

UNLABELLED: Although dopamine receptor antagonism has long been associated with impairments in motor performance, more recent studies have shown that dopamine D2 receptor (D2R) antagonism, paired with a motor task, not only impairs motor performance concomitant with the pharmacodynamics of the drug, but also impairs future motor performance once antagonism has been relieved. We have termed this phenomenon "aberrant motor learning" and have suggested that it may contribute to motor symptoms in movement disorders such as Parkinson's disease (PD). Here, we show that chronic nicotine (cNIC), but not acute nicotine, treatment mitigates the acquisition of D2R-antagonist-induced aberrant motor learning in mice. Although cNIC mitigates D2R-mediated aberrant motor learning, cNIC has no effect on D1R-mediated motor learning. ß2-containing nicotinic receptors in dopamine neurons likely mediate the protective effect of cNIC against aberrant motor learning, because selective deletion of ß2 nicotinic subunits in dopamine neurons reduced D2R-mediated aberrant motor learning. Finally, both cNIC treatment and ß2 subunit deletion blunted postsynaptic responses to D2R antagonism. These results suggest that a chronic decrease in function or a downregulation of ß2-containing nicotinic receptors protects the striatal network against aberrant plasticity and aberrant motor learning induced by motor experience under dopamine deficiency. SIGNIFICANCE STATEMENT: Increasingly, aberrant plasticity and aberrant learning are recognized as contributing to the development and progression of movement disorders. Here, we show that chronic nicotine (cNIC) treatment or specific deletion of ß2 nicotinic receptor subunits in dopamine neurons mitigates aberrant motor learning induced by dopamine D2 receptor (D2R) blockade in mice. Moreover, both manipulations also reduced striatal dopamine release and blunt postsynaptic responses to D2R antagonists. These results suggest that chronic downregulation of function and/or receptor expression of ß2-containing nicotinic receptors alters presynaptic and postsynaptic striatal signaling to protect against aberrant motor learning. Moreover, these results suggest that cNIC treatment may alleviate motor symptoms and/or delay the deterioration of motor function in movement disorders by blocking aberrant motor learning.